Data from FDA - Curated by Toby Galbraith - Last updated 01 January 2017
4 CONTRAINDICATIONS ABSTRAL is contraindicated in: Opioid non-tolerant patients: Life threatening respiratory depression and death could occur at any dose in opioid non-tolerant patients [see Indications and Usage (1); Warnings and Precautions (5.1)]. Acute or postoperative pain, including headache/migraine, dental pain, or use in the emergency department. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9)] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.14)] Known hypersensitivity to fentanyl (e.g., anaphylaxis) [see Adverse Reactions (6.2)]. Opioid non-tolerant patients. (4) Management of acute or postoperative pain including headache/migraines dental pain, or use in the emergency department. (4) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. (4) Known or suspected gastrointestinal obstruction, including paralytic ileus. (4) Known hypersensitivity to fentanyl or components of ABSTRAL. (4)
6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Life-Threatening Respiratory Depression [see Warnings and Precautions (5.1)] Interactions with Benzodiazepines and Other CNS Depressants [see Warnings and Precautions(5.4) Addiction, Abuse, and Misuse [see Warnings and Precautions (5.6)] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.8)] Serotonin Syndrome [see Warnings and Precautions 5.10] Adrenal Insufficiency [see Warnings and Precautions (5.11)] Severe Hypotension [see Warnings and Precautions (5.12)] Gastrointestinal Adverse Reactions [see Warnings and Precautions(5.14)] Seizures [see Warnings and Precautions (5.15)] Most common (total frequency ≥3%): nausea, somnolence, headache, and constipation. (6) To report SUSPECTED ADVERSE REACTIONS, contact Sentynl at 1-888-227-8725 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of ABSTRAL has been evaluated in 311 opioid-tolerant cancer patients with breakthrough pain. Two hundred and seventy (270) of these patients were treated in multiple-dose studies. The duration of therapy for patients in multiple-dose studies ranged from 1-405 days with an average duration of 131 days and with 44 patients treated for at least 12 months. The clinical trials of ABSTRAL were designed to evaluate safety and efficacy in treating patients with cancer and breakthrough pain; all patients were taking concomitant opioids, such as sustained-release morphine, sustained-release oxycodone or transdermal fentanyl, for their persistent pain. The adverse reaction data presented in Table 2 reflect the actual percentage of patients experiencing reactions among patients who received ABSTRAL for breakthrough pain along with concomitant opioid use for persistent pain. There has been no attempt to correct for concomitant use of other opioids, duration of ABSTRAL therapy or cancer-related symptoms. Table 2 lists adverse reactions with an overall frequency of 5% or greater within the total populationthat occurred during titration by maximum dose received. The ability to assign ABSTRAL a dose-response relationship to these adverse reactions is limited by the titration schemes used in thesestudies. Table 2: Adverse Reactions Which Occurred During Titration at a Frequency of ≥ 5% System Organ Class Preferred term N (%) 100 mcg (n=22) 200 mcg (n=23) 300 mcg (n=55) 400 mcg (n=38) 600 mcg (n=52) 800 mcg (n=80) Total (n=270) Gastrointestinal disorders Nausea 1 (4.5) 4 (17.4) 5 (9.1) 1 (2.6) 2 (3.8) 2 (2.5) 15 (5.6) Nervous system disorders Somnolence 0 2 (8.7) 4 (7.3) 2 (5.3) 2 (3.8) 2 (2.5) 12 (4.4) Dizziness 0 0 3 (5.5) 2 (5.3) 0 1 (1.3) 6 (2.2) Headache 0 0 0 1 (2.6) 3 (5.8) 1 (1.3) 5 (1.9) Table 3 lists, by successful dose, adverse reactions with an overall frequency of ≥ 5% within thetotal population that occurred after a successful dose had beendetermined. Table 3: Adverse Reactions Which Occurred During Maintenance Therapy at a Frequency of ≥ 5% System Organ Class Preferred term, N (%) 100 mcg (n=7) 200 mcg (n=12) 300 mcg (n=22) 400 mcg (n=20) 600 mcg (n=35) 800 mcg (n=72) Total (n=168) Gastrointestinal disorders Nausea 1 (14.3) 0 2 (9.1) 0 1 (2.9) 6 (8.3) 10 (6.0) Stomatitis 0 1 (8.3) 1 (4.5) 0 0 1 (1.4) 3 (1.8) Constipation 0 0 1 (4.5) 2 (10.0) 1 (2.9) 4 (5.6) 8 (4.8) Dry mouth 0 0 0 1 (5.0) 2 (5.7) 0 3 (1.8) Nervous system disorders Headache 0 0 0 2 (10.0) 1 (2.9) 2 (2.8) 5 (3.0) Dysgeusia 1 (14.3) 0 0 0 0 1 (1.4) 2 (1.2) General disorders and administration site conditions Fatigue 0 0 0 1 (5.0) 2 (5.7) 0 3 (1.8) Injury, poisoning and procedural complications Accidental overdose 1 (14.3) 0 0 0 0 0 1 (0.6) Respiratory, thoracic and mediastinal disorders Dyspnoea 0 1 (8.3) 0 0 0 0 1 (0.6) Skin and subcutaneous disorders Hyperhidrosis 1 (14.3) 0 0 0 0 1 (1.4) 2 (1.2) The frequencies listed below represent adverse reactions that occurred in ≥1% of patients from two clinical trials who experienced that reaction while receiving ABSTRAL. Reactions are classified by system organ class. Adverse Reactions (≥ 1%) Cardiac disorders: bradycardia, tachycardia. Eye disorders: vision blurred. Gastrointestinal disorders: abdominal pain, abdominal pain upper, aphthous stomatitis, constipation, dry mouth, dyspepsia, gingival ulceration, impaired gastric emptying, lip ulceration, mouth ulceration, nausea, stomach discomfort, stomatitis, tongue disorder, vomiting. General disorders and administration site conditions: asthenia, drug withdrawal syndrome, fatigue, malaise. Immune system disorders: drug hypersensitivity. Injury, poisoning and procedural complications: accidental overdose. Metabolism and nutrition disorders: anorexia, decreased appetite. Nervous system disorders: amnesia, disturbance in attention, dizziness, dysgeusia, headache, hypoesthesia, lethargy, parosmia, somnolence, tremor. Psychiatric disorders: affect lability, anxiety, confusional state, depression, disorientation, dysphoria, euphoric mood, insomnia, mental status changes, paranoia, sleep disorder. Reproductive system and breast disorders: erectile dysfunction. Respiratory, thoracic and mediastinal disorder: dyspnea, oropharyngeal pain, throat tightness. Skin and subcutaneous disorders: hyperhidrosis, night sweats, pruritus, rash, skin lesion. Vascular disorders: hypotension. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fentanyl. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serotonin Syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal Insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in ABSTRAL. Androgen Deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.
Dosing and administration
2 DOSAGE AND ADMINISTRATION Patients must require and use around-the-clock opioids when taking ABSTRAL. (1) Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. Individualize dosing based on the severity of pain, patient response, prior analgesic experience, and risk factors for addiction, abuse, and misuse. (2.1) Administer on the floor of the mouth directly under the tongue and allow to completely dissolve. (2.4) Initial dose of ABSTRAL: 100 mcg. (2.2) No more than two doses can be taken per breakthrough pain episode. (2.2) Individually titrate to a tolerable dose that provides adequate analgesia. (2.3) Wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL. (2.3) Limit consumption to treat four or fewer breakthrough pain episodes per day once a successful dose is found. (2.3) When opioid therapy is no longer required, consider discontinuing ABSTRAL along with a gradual downward of other opioids to minimize possible withdrawal effects. (2.5) 2.1 Important Dosage and Administration Information Healthcare professionals who prescribe ABSTRAL on an outpatient basis must enroll in the TIRF REMS Access program and comply with the requirements of the REMS to ensure safe use of ABSTRAL [see Warnings and Precautions (5.7)]. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. It is important to minimize the number of strengths available to patients at any time to prevent confusion and possible overdose. Initiate the dosing regimen for each patient individually, taking into account the patient's severity of pain, patient response, prior analgesic treatment experience, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.6)]. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy and following dosage increases with ABSTRAL and adjust the dosage accordingly [see Warnings and Precautions (5.1)]. Instruct patients and caregivers to take steps to store ABSTRAL securely and to properly dispose of unused ABSTRAL as soon as no longer needed [see Warnings and Precautions (5.2, 5.6), Patient Counseling Information (17)]. ABSTRAL is not bioequivalent with other fentanyl products. Do not convert patients on a mcg per mcg basis from other fentanyl products. There are no conversion directions available for patients on any other fentanyl products other than Actiq. (Note: This includes oral, transdermal, or parenteral formulations of fentanyl.) [see Warnings and Precautions (5.5)]. ABSTRAL is NOT a generic version of any other oral transmucosal fentanyl product. 2.2 Initial Dosage Initiate treatment with ABSRTAL for all patients with a single initial dose of 100 mcg. The initial dose of ABSTRAL is always 100 mcg, with the only exception being patients already using Actiq. If adequate analgesia is obtained within 30 minutes of administration of the 100 mcg tablet, continue to treat subsequent episodes of breakthrough pain with this dose. If adequate analgesia is not obtained after ABSTRAL, the patient may use a second ABSTRAL dose (after 30 minutes) as directed by their healthcare provider. No more than two doses of ABSTRAL may be used to treat an episode of breakthrough pain. [see Titration and Maintenances of Therapy (2.3)] Patients must wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL. Due to differences in the pharmacokinetic properties and individual variability, even patients switching from other fentanyl containing products to ABSTRAL must start with the 100 mcg dose except patients switching from ACTIQ. ABSTRAL is not equivalent on a mcg per mcg basis with all other fentanyl products, therefore, do not switch patients on a mcg per mcg basis from any other fentanyl product. ABSTRAL is NOT a generic version of any other fentanylproduct. Conversion of ABSTRAL from Actiq For patients being converted from Actiq, prescribers must use the Initial Dosing Recommendations for Patients on Actiq. See Table 1 for initial dosing recommendations. Patients must be instructed to stop the use of Actiq and dispose of any remaining units. Table 1: Initial Dosing Recommendations for Patients on ACTIQ Current ACTIQ Dose (mcg) Initial ABSTRAL Dose (mcg) 200 100 400 200 600 200 800 200 1200 200 1600 400 For patients converting from Actiq doses of 200 mcg and 400 mcg, initiate titration with 100 mcg and 200 mcgof ABSTRAL, respectively and proceed using multiples of this strength. For patients converting from Actiq doses of 600 and 800 mcg, initiate titration with 200 mcg and 200 mcg ABSTRAL, respectively and proceed using multiples of this strength. For patients converting from Actiq doses of 1200 and 1600 mcg, initiate titration with 200 mcg and 400 mcg ABSTRAL, respectively and proceed using multiples of this strength. 2.3 Titration and Maintenance of Therapy Titration The objective of dose titration is to identify an effective and tolerable maintenance dose. From an initial dose, closely follow patients and change the dosage strength until the patient reaches a dose that provides adequate analgesia using a single ABSTRAL dosage unit per breakthrough cancer pain episode. If signs of excessive opioid effects appear before the unit is consumed, the dosage unit should be removed from the patient's mouth immediately, disposed of properly, and subsequent doses should be decreased. Patients should record their use of ABSTRAL over several episodes of breakthrough cancer pain and review their experience with their healthcare providers to determine if a dosage adjustment is warranted for management of breakthrough cancer pain episodes. The effective and tolerable dose of Abstral will be determined by dose titration in individual patients. If adequate analgesia was not obtained with the first 100 mcg dose, continue dose escalation in a stepwise manner over consecutive breakthrough episodes until adequate analgesia with tolerable side effects is achieved. Increase the dose by 100 mcg multiples up to 400 mcg as needed. If adequate analgesia is not obtained with a 400 mcg dose, the next titration step is 600 mcg. If adequate analgesia is not obtained with a 600 mcg dose, the next titration step is 800 mcg. During titration, patients can be instructed to use multiples of 100 mcg tablets and/or 200 mcg tablets for any single dose. Instruct patients not to use more than 4 tablets at one time. If adequate analgesia is not obtained 30 minutes after the use of ABSTRAL, the patient may repeat the same dose of ABSTRAL. No more than two doses of ABSTRAL may be used to treat an episode of breakthrough pain. Rescue medication as directed by the health care provider can be used if adequate analgesia is not achieved after use of ABSTRAL. The efficacy and safety of doses higher than 800 mcg have not been evaluated in clinical studies in patients. In order to minimize the risk of ABSTRAL-related adverse reactions and to identify the appropriate dose, it is imperative that patients be supervised closely by health professionals during the titration process. Figure Maintenance Therapy Once titrated to an effective dose, instruct patients to use only one ABSTRAL tablet of the appropriate strength per dose. Maintain patients on thisdose. If adequate analgesia is not obtained after use of ABSTRAL, the patient may use a second ABSTRAL dose (after 30 minutes) as directed by their healthcare provider. No more than two doses of ABSTRAL maybe used to treat an episode of breakthrough pain. Patients must wait at least 2 hours before treating another episode of breakthrough pain with ABSTRAL. Dose Re-Adjustment If the response (analgesia or adverse reactions) to the titrated ABSTRAL dose markedly changes, an adjustment of dose may be necessary to ensure that an appropriate dose is maintained. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the ABSTRAL dosage. If unacceptable opioid-related adverse reactions are observed, consider reducing the dosage. Adjust the dosage to obtain an appropriate balance between management of breakthrough pain and opioid-related adverse reactions. If more than four episodes of breakthrough pain are experienced per day, re-evaluate the dose of the long- acting opioid used for persistent underlying cancer pain. If the long-acting opioid or dose of long-acting opioid is changed, re-evaluate and re-titrate the ABSTRAL dose as necessary to ensure the patient is on an appropriate dose. Limit the use of ABSTRAL to treat four or fewer episodes of breakthrough pain perday. It is imperative that any dose re-titration is monitored carefully by a healthcare professional. 2.4 Administration of ABSTRAL Instruct patients to place ABSTRAL tablets on the floor of the mouth directly under the tongue immediately after removal from the blister unit and not to chew, suck, or swallow ABSTRAL tablets. Allow ABSTRAL tablets to completely dissolve in the sublingual cavity. Advise patients not to eat or drink anything until the tablet is completely dissolved. In patients who have a dry mouth, water may be used to moisten the buccal mucosa before taking ABSTRAL. 2.5 Discontinuation of ABSTRAL For patients no longer requiring opioid therapy, consider discontinuing ABSTRAL along with a gradual downward titration of other opioids to minimize possible withdrawal effects. In patients who continue to take their chronic opioid therapy for persistent pain but no longer require treatment for breakthrough pain, ABSTRAL therapy can usually be discontinued immediately. 2.6 Disposal of ABSTRAL Patients and their household members must be advised to dispose of any tablets remaining from a prescription as soon as they are no longer needed. Instructions are included in Patient Counseling Information (17) and in the Medication Guide. To dispose of any unused ABSTRAL tablets, remove them from the blister cards and flush down the toilet. Do not dispose of the ABSTRAL blister cards or cartons down the toilet. If additional assistance is required, call 1-888-227-8725.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. (8.1) Lactation: Not Recommended. (8.2) Renal and Hepatic Impairment: Administer ABSTRAL with caution. (8.6) 8.1 Pregnancy - Category C There are no adequate and well-controlled studies in pregnant women. Risk Summary: Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. Available data with ABSTRAL in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In animal reproduction studies, fentanyl administration to pregnant rats during organogenesis was embryocidal at doses within the range of the human recommended dosing. When administered during gestation through lactation fentanyl administration to pregnant rats resulted in reduced pup survival at doses within the range of the human recommended dosing. No evidence of malformations were noted in animal studies completed to date [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy can occur regardless of the heath of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset of neonatal withdrawal symptoms usually occurs in the first days after birth. The duration and severity of neonatal opioid withdrawal syndrome may vary. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.8)]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. ABSTRAL is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ABSTRAL, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data In women treated acutely with intravenous or epidural fentanyl during labor, symptoms of neonatal respiratory or neurological depression were no more frequent than would be expected in infants of untreated mothers. Transient neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl. Animal Data Fentanyl has been shown to embryocidal in pregnant rats at doses of 30 mcg/kg intravenously (0.4 times the 800 mcg dose of ABSTRAL on a mg/m2 basis) and 160 mcg/kg subcutaneously (2 times the 800 mcg dose of ABSTRAL based on a mg/m2 basis). There was no evidence of teratogenicity reported. No evidence of malformations or adverse effects on the fetus was reported in a published study in which pregnant rats were administered fentanyl continuously via subcutaneously implanted osmotic minipumps at doses of 10, 100, or 500 mcg/kg/day starting 2-weeks prior to breeding and throughout pregnancy. The high dose was approximately 6 times the human dose of 800 mcg ABSTRAL per pain episode on a mg/m2 basis and produced mean steady-state plasma levels that are 6 times higher than the mean Cmax observed following administration of 800 mcg dose of ABSTRAL in humans. 8.2 Lactation Risk Summary Fentanyl is present in breast milk. One published lactation study reports a relative infant dose of fentanyl of 0.024%. However, there is insufficient information to determine the effects of fentanyl on the breastfed infant and the effects of fentanyl on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, advise patients that breastfeeding is not recommended during treatment with ABSTRAL. Clinical Considerations Monitor infants exposed to ABSTRAL through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.3 Females and Males of Reproductive Potential Infertility Chronic use of opioids may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.1), Clinical Pharmacology (12.2), Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and efficacy of ABSTRAL have not been established in patients below 18 years of age. 8.5 Geriatric Use Of the 270 opioid tolerant patients with breakthrough cancer pain in the Phase 3 clinical studies of ABSTRAL, 58 (21%) were 65 years of age and older. There was no difference in the median titrated dose in patients aged 65 years and older compared to those <65 years. No clinically meaningful difference was noted in the safety profile of the group 65 years of age and older as compared to younger patients in ABSTRAL clinical trials. Elderly patients have been shown to be more sensitive to the effects of fentanyl when administered intravenously, compared with the younger adult population. Therefore, exercise caution when individually titrating ABSTRAL in elderly patients to provide adequate efficacy while minimizing risk. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co- administered with other agents that depress respiration. Titrate the dosage of ABSTRAL slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9)]. Fentanyl is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Patients with Renal and Hepatic Impairment Insufficient information exists to make recommendations regarding the use of ABSTRAL in patients with impaired renal or hepatic function. Fentanyl is metabolized primarily via human cytochrome P450 3A4 isoenzyme system and the inactive metabolite is mostly eliminated in urine. If the drug is used in these patients, use the drug with caution because of the reduced hepatic metabolism and renal excretion capacity in such patients. 8.7 Sex Both male and female opioid-tolerant cancer patients were studied for the treatment of breakthrough cancer pain. No clinically relevant sex differences were noted either in efficacy or in observed adverse reactions.
|Date Last Revised||16-12-2016|
|Type||HUMAN PRESCRIPTION DRUG|
|Marketing authorisation holder||Sentynl Therapeutics, Inc.|
|Warnings||WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISK FROM CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME WARNING: LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; CYTOCHROME P450 3A4 INTERACTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; RISK OF MEDICATION ERRORS; ADDICTION, ABUSE, AND MISUSE; REMS; and NEONATAL OPIOID WITHDRAWAL SYNDROME See full prescribing information for complete boxedwarning. Serious, life-threatening, and/or fatal respiratory depression has occurred. Monitor closely, especially upon initiation or following a dose increase. ABSTRAL is contraindicated in opioid non-tolerant patients (1) and in management of acute or postoperative pain, including headache/migraines. (4, 5.1) Accidental ingestion of ABSTRAL, especially by children, can result in a fatal overdose of fentanyl. Keep out of reach of children. Ensure proper storage and disposal. (2.6, 5.2) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of fentanyl (5.3, 7) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation (5.4). When prescribing, do not convert patients on a mcg per mcg basis from any other oral transmucosal fentanyl product to ABSTRAL. (2.2, 5.5) When dispensing, do not substitute with any other fentanyl products. (5.5) ABSTRAL exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and monitor closely for these behaviors and conditions. (5.6) ABSTRAL is available only through a restricted program called the TIRF REMS Access program. Outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors are required to enroll in the program. (5.7) Prolonged use of ABSTRAL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If prolonged opioid use is required in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.8) Life-Threatening Respiratory Depression Serious, life-threatening and/or fatal respiratory depression has occurred in patients treated with ABSTRAL, including following use in opioid non-tolerant patients and improper dosing. Monitor for respiratory depression, especially during initiation of ABSTRAL or following a dose increase. The substitution of ABSTRAL for any other fentanyl product may result in fatal overdose. [see Warnings and Precautions (5.1)]. Due to the risk of respiratory depression, ABSTRAL is contraindicated in the management of acute or postoperative pain including headache/migraine and in opioid non-tolerant patients. [see Contraindications (4)] Accidental Ingestion Accidental ingestion of even one dose of ABSTRAL, especially by children, can result in a fatal overdose of fentanyl [see Warnings and Precautions (5.2)]. Death has been reported in children who have accidentally ingested transmucosal immediate-release fentanyl products. ABSTRAL must be kept out of reach of children. [see Warnings and Precautions (5.2); Patient Counseling Information (17) and Storage and Handling (16)] Cytochrome P450 3A4 Interaction The concomitant use of ABSTRAL with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving ABSTRAL and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.3), Drug Interactions (7), Clinical Pharmacology (12)]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.4), Drug Interactions (7) ]. Reserve concomitant prescribing of ABSTRAL and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required Follow patients for signs and symptoms of respiratory depression and sedation Risk of Medication Errors Substantial differences exist in the pharmacokinetic profile of ABSTRAL compared to other fentanyl products that result in clinically important differences in the extent of absorption of fentanyl and that could result in fatal overdose [see Dosage and Administration (2.1), Warnings and Precautions (5.5)]. When prescribing, do not convert patients on a mcg per mcg basis from any other fentanyl products to ABSTRAL. When dispensing, do not substitute an ABSTRAL prescription for other fentanyl products. Addiction, Abuse, and Misuse ABSTRAL exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient's risk prior to prescribing ABSTRAL, and monitor all patients regularly for the development of these behaviors and conditions [ see Warnings and Precautions (5.6) ]. Risk Evaluation and Mitigation Strategy (REMS) Access Program Because of the risk for misuse, abuse, addiction, and overdose, ABSTRAL is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Under the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access program, outpatients, healthcare professionals who prescribe to outpatients, pharmacies, and distributors must enroll in the program. [see Warnings and Precautions (5.7)] Further information is available at www.TIRFREMSAccess.com or by calling 1-866-822-1483. Neonatal Opioid Withdrawal Syndrome Prolonged use of ABSTRAL during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.8)].|